THORPE, PHILIP E. Our goal is to develop new, broad spectrum anti-viral agents for the treatment of hemorrhagic fevers caused by hostile dissemination of NIAID category A arenaviruses. The new agents are antibodies that recognize normally-internal phospholipids (e.g. phosphatidylserine, PS) that become exposed on the surface of virally infected cells shortly after infection. PS is also present on the outer envelope of multiple viruses. We previously generated a human-mouse chimeric antibody called bavituximab, that binds PS through a PS-binding plasma protein, 2-glycoprotein 1 ( 2GP1). Bavituximab cured guinea pigs lethally infected with Pichinde virus (a model of Lassa fever). It also protected mice from lethal challenge with mCMV. However, it was discovered in clinical trials that bavituximab is immunogenic. Repeated treatment of humans induced antichimeric antibody responses against murine components of the antibody. In this grant application, we propose to evaluate a panel of fully human anti-PS antibodies that are less likely to evoke immune reactions in humans. The panel has already been generated in collaboration with our industrial partner Peregrine Pharmaceuticals, Inc. It consists of: 1) fully human bavituxiimab equivalents that cross-block bavituximab;2) fully human antibodies that recognize non-crossblocking epitopes on 2GP1;3) fully human antibodies that bind PS directly. The binding of the antibodies to immobilized antigens, virions and virally-infected cells will be characterized. The antibodies will be compared for their ability to protect guinea pigs from lethal Pichinde virus infections. Safety and toxicological parameters will be established. The lead therapeutic candidate antibody will be identified as having the best anti-viral activity, combined with minimal or no toxicity. These studies will promote further development of anti-PS antibodies for the treatment of human hemorrhagic arenavirus infections.